Amlodipine besylate/Valsartan/Hydrochlorothiazide

Description

Amlodipine, valsartan and hydrochlorothiazide tablets USP are a fixed combination formulation containing amlodipine besylate, valsartan, and hydrochlorothiazide. Amlodipine besylate, a dihydropyridine calcium channel blocker, is presented as a white or almost white powder, with a chemical name of 3-Ethyl 5-methyl (±)-2-(2-aminoethoxy)methyl-4-(o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulfonate. Its molecular formula is C20H25ClN2O5 • C6H6O3S, and it has a molecular weight of 567.1.

Valsartan, a nonpeptide angiotensin II antagonist, is characterized as a white, fine hygroscopic powder. Its chemical name is N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl) 1,1′-biphenyl-4-yl]methyl]-L-valine, with a molecular formula of C24H29N5O3 and a molecular weight of 435.5. Hydrochlorothiazide, a thiazide diuretic, is a white or practically white crystalline powder, described chemically as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its molecular formula is C7H8ClN3O4S2, and it has a molecular weight of 297.73.

The tablets are available in film-coated forms containing amlodipine besylate USP at dosages of 6.9 mg or 13.9 mg (equivalent to 5 mg or 10 mg of amlodipine, respectively), valsartan USP at 160 mg or 320 mg, and hydrochlorothiazide USP at 12.5 mg or 25 mg. The available combinations include 5 mg/160 mg/12.5 mg, 10 mg/160 mg/12.5 mg, 5 mg/160 mg/25 mg, 10 mg/160 mg/25 mg, and 10 mg/320 mg/25 mg. Inactive ingredients across all strengths consist of colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch (maize), sodium starch glycolate, talc, and titanium dioxide. Specific strengths also contain color additives such as red iron oxide and yellow iron oxide. The USP Organic Impurities Test is pending.

Uses and Indications

Amlodipine, valsartan, and hydrochlorothiazide tablets are indicated for the treatment of hypertension to lower blood pressure. The reduction of blood pressure is associated with a decreased risk of both fatal and nonfatal cardiovascular events, including strokes and myocardial infarctions.

Limitations of use: Amlodipine, valsartan, and hydrochlorothiazide tablets are not indicated for the initial treatment of hypertension.

There are no teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

The recommended dosage for Amlodipine, Valsartan, and Hydrochlorothiazide tablets is once daily. Healthcare professionals should titrate the dose as necessary, with a maximum allowable dose of 10 mg of amlodipine, 320 mg of valsartan, and 25 mg of hydrochlorothiazide.

These tablets may be utilized as add-on or switch therapy for patients who are not adequately controlled on any two of the following antihypertensive classes: calcium channel blockers, angiotensin receptor blockers, and diuretics. Additionally, Amlodipine, Valsartan, and Hydrochlorothiazide tablets can be substituted for their individually titrated components, ensuring that the overall therapeutic regimen remains effective and tailored to the patient's needs.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with anuria, as the drug's mechanism may not be effective in the absence of urine production.

Individuals with hypersensitivity to sulfonamide-derived drugs or any component of the formulation, due to the risk of severe allergic reactions.

Coadministration of aliskiren with amlodipine, valsartan, and hydrochlorothiazide tablets is contraindicated in patients with diabetes, as this combination may increase the risk of adverse effects.

Warnings and Precautions

Fetal toxicity is a significant concern associated with the use of amlodipine, valsartan, and hydrochlorothiazide. It is imperative that these medications be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system may cause injury or death to the developing fetus.

Healthcare professionals should exercise caution regarding hypotension. It is essential to correct any volume depletion prior to initiating treatment with these agents. Patients may experience increased angina or myocardial infarction, necessitating careful monitoring of their cardiovascular status.

In susceptible patients, renal function and potassium levels should be closely monitored to prevent complications. Additionally, there is a risk of exacerbation or activation of systemic lupus erythematosus, which requires vigilance in monitoring for any related symptoms. Healthcare providers should also observe patients for signs of fluid or electrolyte imbalance, as these can lead to further complications.

Acute angle-closure glaucoma is another potential risk associated with these medications, and appropriate measures should be taken to mitigate this risk in at-risk populations. Regular laboratory tests to monitor renal function and potassium levels are recommended for patients who may be susceptible to these adverse effects.

Side Effects

Patients receiving treatment with amlodipine, valsartan, and hydrochlorothiazide may experience a range of adverse reactions. The most common adverse events, occurring in 2% or more of participants, include dizziness, peripheral edema, headache, dyspepsia, fatigue, muscle spasms, back pain, nausea, and nasopharyngitis.

Serious warnings associated with this medication include fetal toxicity. It is imperative to discontinue the use of amlodipine, valsartan, and hydrochlorothiazide as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Additional adverse reactions of clinical significance include hypotension, which necessitates correction of volume depletion prior to initiation of therapy. Patients may also experience increased angina and/or myocardial infarction, and it is recommended to monitor renal function and potassium levels in susceptible individuals. There have been reports of exacerbation or activation of systemic lupus erythematosus, as well as acute angle-closure glaucoma.

Patients should be observed for signs of fluid or electrolyte imbalance, and anuria has been noted as a potential adverse effect. Hypersensitivity reactions may occur, particularly in individuals with known hypersensitivity to sulfonamide-derived drugs or any component of the formulation. Furthermore, coadministration of aliskiren with amlodipine, valsartan, and hydrochlorothiazide is contraindicated in patients with diabetes.

Drug Interactions

Coadministration of simvastatin with amlodipine should not exceed a daily dose of 20 mg of simvastatin due to the potential for increased risk of adverse effects.

When antidiabetic drugs are used concurrently, dosage adjustments may be necessary to maintain glycemic control.

The use of cholestyramine or colestipol can lead to reduced absorption of thiazide diuretics, which may diminish their therapeutic efficacy.

Concurrent use of lithium increases the risk of lithium toxicity; therefore, it is essential to monitor serum lithium concentrations closely during this combination therapy.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) may elevate the risk of renal impairment and can diminish the antihypertensive effects of certain medications.

Additionally, dual inhibition of the renin-angiotensin system poses an increased risk of renal impairment, hypotension, and hyperkalemia, necessitating careful monitoring of renal function and electrolyte levels in patients receiving such combinations.

Packaging & NDC

The table below lists all NDC Code configurations of Amlodipine, Valsartan and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of amlodipine, valsartan, and hydrochlorothiazide in pediatric patients have not been established. Therefore, caution is advised when considering the use of these medications in children and adolescents. Further studies are necessary to determine appropriate dosing and outcomes in this population.

Geriatric Use

Clinical studies of amlodipine besylate tablets did not include a sufficient number of subjects aged 65 and over to determine whether these elderly patients respond differently from younger individuals. However, other reported clinical experiences have not identified significant differences in responses between geriatric patients and their younger counterparts.

In general, dose selection for elderly patients should be approached with caution. It is advisable to start at the lower end of the dosing range, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

Elderly patients exhibit decreased clearance of amlodipine, leading to an increase in the area under the curve (AUC) of approximately 40% to 60%. It is important to note that the recommended starting dose of 2.5 mg of amlodipine is not available in the combination formulation of amlodipine, valsartan, and hydrochlorothiazide. Therefore, careful consideration and monitoring are essential when prescribing this medication to geriatric patients.

Pregnancy

Amlodipine, valsartan, and hydrochlorothiazide are associated with potential fetal harm when administered to pregnant patients. The use of medications that act on the renin-angiotensin system during the second and third trimesters can lead to reduced fetal renal function, increasing the risk of fetal and neonatal morbidity and mortality. Epidemiologic studies examining fetal abnormalities following antihypertensive use in the first trimester have not consistently differentiated between drugs affecting the renin-angiotensin system and other antihypertensive agents.

Published reports indicate cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan. When pregnancy is confirmed, it is recommended to discontinue amlodipine, valsartan, and hydrochlorothiazide as soon as possible. The estimated background risk of major birth defects and miscarriage in the general U.S. population is 2 to 4% and 15 to 20%, respectively; however, the specific background risk for the indicated population remains unknown. All pregnancies carry a baseline risk of birth defects, loss, or other adverse outcomes.

Hypertension during pregnancy poses increased maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and complications during delivery, such as the need for cesarean section and postpartum hemorrhage. Additionally, hypertension elevates the fetal risk for intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be closely monitored and managed appropriately.

The occurrence of oligohydramnios in pregnant women using drugs that affect the renin-angiotensin system during the second and third trimesters can lead to severe fetal complications, including reduced renal function, anuria, renal failure, fetal lung hypoplasia, skeletal deformations, hypotension, and death. Serial ultrasound examinations are recommended to assess the intra-amniotic environment, and fetal testing may be warranted based on gestational age. It is crucial for patients and healthcare providers to recognize that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. If oligohydramnios is detected, alternative drug treatments should be considered.

Neonates with a history of in utero exposure to amlodipine, valsartan, and hydrochlorothiazide should be closely observed for hypotension, oliguria, and hyperkalemia. In cases of oliguria or hypotension, supportive measures for blood pressure and renal perfusion may be necessary, and interventions such as exchange transfusions or dialysis may be required to restore renal function.

Hydrochlorothiazide, like other thiazide diuretics, crosses the placenta, with umbilical vein concentrations approaching those in maternal plasma. It can accumulate in amniotic fluid, with reported concentrations significantly higher than in umbilical vein plasma. The use of thiazides during pregnancy is associated with risks of fetal or neonatal jaundice and thrombocytopenia. Given that these medications do not prevent or alter the course of edema, proteinuria, and hypertension (EPH) gestosis (preeclampsia), their use for treating hypertension in pregnant women is not recommended. Furthermore, the use of hydrochlorothiazide for other indications, such as heart disease, during pregnancy should also be avoided.

Lactation

There is no specific information available regarding the use of this medication in nursing mothers. Additionally, there is no data on the potential for excretion of this medication in breast milk or its effects on breastfed infants. Healthcare professionals should consider the lack of information when advising lactating mothers about the use of this medication.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored closely. This is particularly important for those with reduced kidney function, as they may be at increased risk for complications. Dosing adjustments may be necessary based on the degree of renal impairment to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Limited data are available regarding overdosage in humans. The most likely manifestations of overdosage include hypotension and tachycardia; bradycardia may occur due to parasympathetic (vagal) stimulation. In the event of symptomatic hypotension, supportive treatment should be initiated.

Animal studies indicate that single oral doses of amlodipine maleate equivalent to 40 mg/kg in mice and 100 mg/kg in rats resulted in fatalities. In dogs, single oral doses equivalent to 4 mg/kg or more (which is 11 or more times the maximum recommended human dose MRHD on a mg/m² basis) led to significant peripheral vasodilation and hypotension. Overdosage is expected to cause excessive peripheral vasodilation, resulting in marked hypotension. Although human experience with intentional overdosage of amlodipine is limited, reports indicate that marked and potentially prolonged systemic hypotension, including shock with fatal outcomes, have occurred.

In cases of massive overdose, active cardiac and respiratory monitoring should be initiated. Frequent blood pressure measurements are essential. If hypotension occurs, cardiovascular support should be provided, which may include elevating the extremities and judicious administration of fluids. Should hypotension remain unresponsive to these conservative measures, the administration of vasopressors, such as phenylephrine, should be considered, with careful attention to circulating volume and urine output. Due to the high protein binding of amlodipine, hemodialysis is unlikely to be beneficial. The administration of activated charcoal to healthy volunteers within two hours of amlodipine ingestion has been shown to significantly reduce amlodipine absorption.

In relation to valsartan, a depressed level of consciousness, circulatory collapse, and shock have been reported. It is important to note that valsartan is not removed from the plasma by hemodialysis. In animal studies, valsartan did not exhibit grossly observable adverse effects at single oral doses up to 2,000 mg/kg in rats and 1,000 mg/kg in marmosets, with the exception of salivation and diarrhea in rats and vomiting in marmosets at the highest doses (60 and 31 times, respectively, the MRHD on a mg/m² basis).

The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The most common signs and symptoms observed in patients following overdosage are those associated with electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may exacerbate cardiac arrhythmias. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, which is 2,000 and 4,000 times, respectively, the MRHD on a mg/m² basis. In studies involving rats and marmosets, single oral doses of valsartan up to 1,524 mg/kg in combination with hydrochlorothiazide at doses up to 476 mg/kg were very well tolerated without any treatment-related effects.

Nonclinical Toxicology

No information is available regarding teratogenic effects.

In studies evaluating non-teratogenic effects, amlodipine maleate demonstrated no impact on the fertility of rats treated orally at doses up to 10 mg amlodipine/kg/day, which is approximately 10 times the maximum recommended human dose (MRHD) of 10 mg/day on a mg/m² basis. Similarly, valsartan did not adversely affect the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day, about 6 times the MRHD on a mg/m² basis. Hydrochlorothiazide also showed no adverse effects on the fertility of mice and rats of either sex when administered via diet at doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation. These doses correspond to approximately 19 and 1.5 times the MRHD on a mg/m² basis, assuming an oral dose of 25 mg/day and a 60-kg patient.

No carcinogenicity, mutagenicity, or fertility studies have been conducted with the combination of amlodipine, valsartan, and hydrochlorothiazide. However, individual studies for each component have been performed. Based on preclinical safety and human pharmacokinetic studies, there is no indication of any toxicologically significant adverse interaction among these components.

In carcinogenicity studies, rats and mice treated with amlodipine maleate in the diet for up to two years at daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day exhibited no evidence of carcinogenic effects. The highest dose for mice was similar to the MRHD of 10 mg amlodipine/day on a mg/m² basis, while for rats, it was approximately 2.5 times the MRHD. Mutagenicity studies with amlodipine maleate indicated no drug-related effects at either the gene or chromosome level.

Valsartan was administered in the diet to mice and rats for up to two years at doses of up to 160 mg/kg/day and 200 mg/kg/day, respectively, with no evidence of carcinogenicity observed. These doses are approximately 2.4 and 6 times the MRHD of 320 mg/day on a mg/m² basis. Mutagenicity assays, including tests with Salmonella and E. coli, a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with Chinese hamster ovary cells, and a rat micronucleus test, did not reveal any valsartan-related effects at the gene or chromosome level.

Two-year feeding studies conducted by the National Toxicology Program (NTP) found no evidence of carcinogenic potential for hydrochlorothiazide in female mice at doses up to approximately 600 mg/kg/day or in male and female rats at doses up to approximately 100 mg/kg/day. However, the NTP reported equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay or in the Chinese Hamster Ovary test for chromosomal aberrations, nor in vivo in assays using mouse germinal cell chromosomes and Chinese hamster bone marrow chromosomes. Positive results were observed in the in vitro CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays, as well as in the Aspergillus Nidulans non-disjunction assay.

Postmarketing Experience

Patients taking hydrochlorothiazide have been advised to protect their skin from sun exposure and to undergo regular skin cancer screenings due to reports of non-melanoma skin cancer associated with the medication. Additionally, it is recommended that patients using amlodipine, valsartan, and hydrochlorothiazide tablets also take similar precautions, as one of the components may contribute to the risk of non-melanoma skin cancer. Patients are encouraged to contact their healthcare provider for medical advice regarding any side effects experienced and are informed that side effects can be reported to the FDA at 1-800-FDA-1088.

Patient Counseling

Advise patients to read the FDA-approved patient labeling (Patient Information) prior to initiating treatment with amlodipine, valsartan, and hydrochlorothiazide, and each time they receive a refill, as there may be new information.

For female patients of childbearing age, it is essential to discuss the potential consequences of exposure to these medications during pregnancy. Healthcare providers should explore alternative treatment options for women planning to become pregnant and encourage patients to report any pregnancies to their physician as soon as possible. Additionally, advise women not to breastfeed while undergoing treatment with amlodipine, valsartan, and hydrochlorothiazide.

Inform patients about the risk of symptomatic hypotension, particularly during the initial days of therapy. Patients should be made aware that lightheadedness may occur and should report this to their healthcare provider. Instruct patients to discontinue the medication and consult their physician if syncope occurs. Caution all patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, resulting in lightheadedness or syncope.

Patients should be advised against using salt substitutes without prior consultation with their healthcare provider, as potassium supplements may interact with the medication. For those taking hydrochlorothiazide, instruct them to protect their skin from sun exposure and to undergo regular skin cancer screenings due to the risk of non-melanoma skin cancer.

Encourage patients to disclose all medical conditions to their healthcare provider, including pregnancy status, breastfeeding plans, allergies to any ingredients in the medication, and any history of heart, liver, or kidney problems. It is also important to inform the provider about any episodes of vomiting or diarrhea, gallstones, lupus, low potassium or magnesium levels, high calcium levels, high uric acid levels, or previous reactions such as angioedema to other blood pressure medications.

Patients should be reminded to inform their healthcare provider about all medications they are taking, including prescription and nonprescription drugs, vitamins, and herbal supplements, as interactions may lead to serious side effects. Maintaining an updated list of medications to share with healthcare providers is advisable.

Instruct patients to take amlodipine, valsartan, and hydrochlorothiazide exactly as prescribed, once daily, with or without food. If a dose is missed, patients should take it as soon as they remember unless it is close to the time of the next dose; in that case, they should skip the missed dose and resume the regular dosing schedule.

In the event of an overdose, patients should contact their healthcare provider, Poison Control Center, or seek emergency medical attention. It is crucial for patients to inform all healthcare providers, including dentists, that they are taking amlodipine, valsartan, and hydrochlorothiazide, especially prior to surgery or kidney dialysis.

Patients should be encouraged to seek medical advice regarding any side effects experienced during treatment and may report side effects to the FDA at 1-800-FDA-1088.

Storage and Handling

The product is supplied in a tight container to ensure its integrity, in accordance with USP standards. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from moisture to maintain its quality and efficacy.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Amlodipine, Valsartan and Hydrochlorothiazide as submitted by Aurobindo Pharma Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)